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Patented Sept. 29, 1931 UNITED STATES PATENT OFFICE KARL MIESCHER, OF BASEL, SWITZERLAND, ASSIGNOR TO THE FIR-M SOCIETY OF CHEMICAL INDUSTRY IN BASLE, OF BASEL, SWITZERLAND DERIVATIVE OF QUINOLINE CARBOXYLIC ACIDS AND PROCESS OF MAKING SAME No'Drawing'. Application filed December 23, 1927, Serial No. 242,281, and in Germany May 3, 1926.

The present invention relates to new substituted basic derivatives of quinoline carboxylic acids useful in therapeutics, and it comprises the new compounds themselves and the process of making them.

The new products are obtained by causing an acid halide of an a-halogen- -quinolinecarboXylic acid to react with an alkylenepolyamine containing simultaneously at least one tertiary basic group and at least one amino group possessing at least one tree hydrogen atom.

There are thus obtained for instance from c-chlo1o -quinoline-carboxylic acid chloride and diethylethylenediamine the oc-ClllOIOyquinoline carboxylic acid diethyl aminoethylene-amide (Formula I.) and from this, by treatment with sodiummethylate in the presence of a solvent, or with an aqueous methyl alcohol solution of an alkali, or with other liydrohalic binding agents the ocmethoxy quinoline-carboxylic acid diethylamino-ethylene-amide (Formula II.)

' c ioNnomomNwinm The new bases yield neutral salts soluble in water; they are characterized by their high therapeutic activity.

The following examples illustrate the invention, the parts being by weight:

I. BASIC CHLono uiNoLrNn-OARBoxYLro Aorn DERIVATIVES Ewample 1 CONHCHzCHzNKJzHsh forms colorless lamina crystals of melting point 74 C. It is easily soluble in most organic solvents. With acids the base forms neutral salts soluble in water.

Ewample 2 Into a solution of 1.5 parts of triethylethylenediamine (colorless base boiling at 160-165 C. and obtained by reducing the condensation product, boiling point l0" under 7 mm. pressure, from unsymmetrical diethylethylenediamine and aeetaldehyde) in 4 parts of caustic soda solution of 10 per cent. strength is run gradually, while stirring and cooling, a benzene solution of 2.2 parts of ozchloro- -quinoline-carboxylic acid chloride. \Vhen the reaction is finished the solution is washed with water and the solvent distilled. The a-ehloro- -quinoline-carboxylie acid-diethyl amino ethylene-ethyl amide of the formula 0 H: 0 ON C1110 IlzN (C2115) Cl N is a yellowish oil boiling at 165 C. at about 0.015 mm. pressure. In organic solvents it is freely soluble; with acids the base yields neutral salts soluble in water.

Example 3 forms colorless crystals of melting point 208 C. It may be recrystallized from alcohol. In ether and benzene it is sparingly soluble; with acids the base yields neutral salts soluble in water.

In analogous manner may be made, for example a-chloro- -quinoline-earboxylic acid-diethylammo penta methylene amide of the formula CIONHCHzCIIzCHgCHgCHzN(02119 colorless crystals, of melting point 55 C.

a-chloro--y-quinoline-carboxylic acid-piperidine-ethylene-amlde of the formula 0 ONHCH3CH1N 011:

onPo in colorless crystals of melting point 147 C.

a-Cl'llOlO-y(1l1l110ll116-C211l)OXyllC acid-bisdiethyl-ammo-ethylene)-1mide of the formula a yellowish oil of boiling point 165470 C.

0.01 mm. pressure.

The bis-(diethylaminoethyl)-imine is obtained, for example, from B-chloro-ethyldiethylamine and ammonia. It is a colorless oil of boiling point 105110 C. under 8 mm. pressure.

II. BASIC ALKOXYQUINOLINE-GARBOXYLIC A011) DERIVATIVES Example 4 15 parts of a-chloro-- -quinolinecarboxylic acid-diethyl-an"1ino-ethylene-amide are boiled with a methyl alcohol solution of 2 parts of sodium hydroxide. The methyl alcohol is 1 then distilled; the residue taken upwith ether and washed with water. After separating the solvent there remains a-methoXy- -quinoline-carboxylie acid-diethyl-amino-ethylene amide of the formulain the form of an oil which soon solidifies to colorless crystals. It can be recrystallized lljU from petroleum ether and melts at 94 C. It is easily soluble in the usual organic solvents and yields with acids neutral salts soluble in i Water.

Example A solution of 2.5 parts of sodium in n-butylalcohol is boiled with parts of oc-Cl1lOIO-yquinoline carboxylic acid diethyl amino ethylene-amide in a reflux apparatus, and when the reaction is over the excess of butylalcohol is distilled. The remaining base is taken up with ether; the solution is washed with water and dried. The solvent is then distilled. The 0; n butoxy- -quinoline-carboxylic acid-diethyl-amino-ethylene amide of the formula oonuomommoznm forms colorless crystals of melting point 64 C. It may be recrystallized from petroleum ether, whereas in other organic solvents it is freely soluble. With acids the base forms neutral salts soluble in water.

Example 6 2.5 parts of sodium are heated with 11 parts of cyclohexanol in parts of toluene. When the reaction is over 30 parts of a-ChlOIO-yquinoline carboxylic acid diethyl aminoethylene-amide are added and the whole is boiled for some time in a refiux'apparatus. The solution is then washed with water and the solvent distilled. The a-cycloheXoxyquinoline carboxylic acid diethyl aminoethylene-amide of the formula CH2CH2 OCH CH2 N GE's-CH2 forms colorless crystals of melting point 69 C. It may be recrystallized from petroleum ether, whereas it is freely soluble in other organic solvents. With acids it forms neutral salts soluble in water.

Example 7 A xylene solution of 3 parts of a-chloroquinoline carboxylic acid diethyl aminoethylene-amide and 1.5 parts of sodium hydroquinone-1nono-methyl-ether is boiled for some time. The solution is then washed with dilute caustic soda solution and the solvent distilled. The ocpara-methoxyphenoxy) quinoline-carboxylic acid diethyl-aminoethylene-amide of the formula C ONHCHzCHzN (CzH5)2 forms colorless crystals of melting point 108 C. It may be recrystallized from petroleum ether, whereas it is freely soluble in other organic solvents. With acids it forms neutral salts soluble in water.

Example 8 C2115 CON I CHzCH2N(CzH5)2 moomom in the form of a yellowish oil of boiling point 158l60 C. at about 0.02 mm. pressure. It is freely soluble in organic solvents. With acids it yields neutral salts soluble in water.

Example A solution of 2.3 parts of sodium in isoamyl alcohol is boiled with 30 parts of oc-ClllOl'O-yquinoline carboxylic acid diethyl aminoethylene-ethyl-amide and when the excess of amyl-alcohol has been distilled the procedure of Example 8 is followed to isolate the prod uct. The a-isoamoxy- -quino1ine-carboxylic acid-diethyl-amino-ethylene-ethyl-amide of the formula CHzCHICIHCIIK forms a yellowish oil of boiling point 165- 168 C. at about 0.01 mm. pressure. It is freely soluble in organic solvents. The base yields with acids neutral salts soluble in water.

Ewamplc 10 OON cmommcma,

is a yellowish oil of boiling Joint 172 C. at about 0.008 mm. pressure. t is freely soluble in organic solvents. The base yields with acids neutral salts soluble in water.

Example 11 An alcoholic solution of 1 part of potassium hydroxide is boiled with parts of ozchloro- -quinoline-carboxylic acid-N-methylpiperazide. The alcohol is distilled and the solid residue washed with water. By recrystallization from alcohol there is obtained the acthoxy 7 quinoline carboxylic acid N methylpiperazide of the formula in the form of colorless crystals of melting point 183 C. In ether and cold alcohol it is sparingly soluble; more freely in Warm alcohol. The base forms with acids neutral salts 4 soluble in water.

In an analogous manner there may also be prepared, for example, the following bases (1) a-ethoxy-y-quinoline-carboxylic diethyl amino-ethylene-amide, crystals of melting point 98 C.

2) a n propoxy y quinoline carboxylic acid-diethyl-aminoethylene-amide, colorless crystals of melting point 63 C.

(3) a-alloxy-y-quinoline-carboxylic acid-diethyl amino ethylene amide, colorless crystals of melting point 57 C.

( t) a-n-amoxy-y-quinoline carboxylic aciddiethyl-amino ethylene amide, colorless crystals of melting point 72 C.

(5) a-isoamoxy- -quinoline-carboxylic aciddiethyl-amino ethylene amide, colorless crystals of melting point 35 C.

(6) a n heptoxy 7 quinoline-carboxylic ac-id-diethyl-amino-ethylene-amide, colorless crystals of melting point 66 C.

(7) a-benzoXy- -quinoline-carboxylic aciddiethyl-amino ethylene amide, colorless crystals of melting point 119 C.

(8) a phenethoxy 7 quinoline-carboxylic acid-diethyl-aminoethylene-amide, colorless crystals of melting point 90 C.

(9) a ethoXy-y quinoline-carboxylic aciddicthyl amino penta methylene amide, colorless crystals of melting point 7 1 C.

(10) a-n-butoxy -y acidcolorless quinoline carboxylic acid piperidinoethylene-amide, colorless crystals of melting point 93 C.

(11) a methoxy 7 quinoline carboxylic acid-diethyl-amino-ethylene-ethyl amide, a yellowish oil of boiling point 150 C. at 0.008 mm. pressure.

(12) a-propoXy- -quinoline-carboxylic aciddiethyl-amino-ethylene-cthyl-amide, a yellowish oil of boiling point 155 C. at 0.008 mm. pressure.

(13) 0: -11 butoxy y quinoline carboxylic acid-diethyLamino-ethylene ethyl-amide, a yellowish oil of boiling point 163 C. at 0.01 mm. pressure.

(1 1) a-n-amoxy-y-quinoline-carboxylic aciddiethylamino-ethylene-ethyl-amide, a yellowish oil of boiling point 175 C. at 0.02

mm. pressure.

(15) a-cycloheXoxy- -quinoline carboxylic acid-diethyl-amino-ethylene-ethyl amide, a yellowish oil of boiling point 185 C. at 0.015 mm. pressure.

16) u-benzoxy-y-quinoline-carboxylic acidtriethylethylenediamide, a yellowish oil, of boiling point 192 C. at 0.01 mm. pressure.

(17) a butoxy-y-quinoline-carboxylic acid- N-methylpiperizide, colorless crystals of melting point 145 C (18) a-ethoxy- -quinoline-carboxylic acid bis-(diethyl-amino-ethylene) -imide, a yellowish oil of boiling point 165 C. at 0.01 mm. pressure.

hat I claim is 1. A process for the manufacture of substituted basic derivatives of quinoline carboxylic acids by causing an acid halide or an ahalogen- -quinoline-carboxylic acid, to react with a base of the formula wherein R stands for hydrogen, alkyl, or dialkylaminoalkyl, and R and R for alkyl, and wherein R and R or R and R may also stand for an alkylene chain to form a heterocyclic siX member ring/in which one or two of the N-atoms will be part of the rin 3. A process for the manufacture of substituted basic derivatives of quinoline carboxyli acids by causing an acid halide of an a-hali gen- -quinoline-carboxylic acid to react with a base of the formula wherein R stands for hydrogen, alkyl or dialkylaminoalkyl.

4. A process for the manufacture of substituted basic derivatives of quinoline carboxylic acids by causing an acid halide of an a-halogen- -quinoline-carboxylic acid, to react with a base of the formula R! 1/3} H N A I\\R:

wherein A represents an alkylene radical containing at least two carbon atoms, R stands for hydrogen, alkyl or dialkylaminoalkyl, and R: and R for alkyl, and wherein R and R or R and R may also stand for an alkyl ene chain to form a heterocyc-lic six member ring in which one or two of the N-atoms will be part of the ring, and causing the basically substituted amides of the halogen-quinolinecarboi ylic acid thus obtained to react with compounds of the formula ROH, R standing for the nionovalent radicals alkyl, alkylene, phcnylalkyl, phenyl or hydrophenyl.

5. A process for the manufacture of. substituted basic derivatives of quinoline carboxylic acids by causing an acid halide of an a-halogen- -qninoline-carboxylic acid to re actwith a base of the formula wherein R stands for hydrogen, alkyl or dialkylaminoalkyl, and R and R for alkyl, and wherein R and R or R and R may also stand for an alkylene chain to form heterocyclic six member rings in which one or two of the N-atoms will be part of the ring, and causing the basically substituted amides of the halogen-quinoline-carboxylic acid thus obtained to react with compounds of the formula R standing for the Inonovalent radicals alkyl, alkylene, phenylalkyl, phenyl, or hydro phenyl.

6. A process for the manufacture of sub stituted basic derivatives of quinoline carboxylic acids by causing an acid halide of an a-halogen- -quin-oline-carboxylic acid to react with a base of the formula wherein R stands for hydrogen, alkyl or dialkylaminoalkyl, and causing the basically substituted amides of the halogen-quinolinecarboxylic acid thus obtained to react with compounds of the formula ROH, R standing for the monovalent radicals alkyl, alkylene, phenylalkyl, phenyl or hydrophenyl.

7. As new products basically substituted alkylene amides of -quinoline-carboxylic acids of the general formula rings in which one or two of the N-atoms will be part of the ring, and wherein R stands for the monovalentradicals alkyl, alkylcue, phenylalkyl, phenyl or hydrophenyl, which products are useful in therapeutics.

8. As new products basically substituted allzylene amides of -quinoline-carboxylic acids of the general formula Rx c ox m I cmcinN wherein R stands for hydrogen, alkyl or dialkylaminoalkyl, and R and R for alkyl,

(I; as

wherein R stands for hydrogen, alkyl or dialkylaminoalkyl and R for the monovalent radicals alkyl, alkylene, phenylalkyl, phenyl or hydrophenyl which products are useful in therapeutics.

10. As new products basically substituted alkylene amides of -quinoline-carboxylic acids of the general formula O n RrHJ N wherein R stands for hydrogen, alkyl or dialkylaminoalkyl and 72 means a whole number, which products are useful in therapeutics. c

11. As new products basically substituted alkylene amides of the a-butoXy- -quinolinecarboxylic acid of the general formula 1 0 ON C2H5 CHaCHzN wherein R stands for hydrogen or alkyl, which products are useful in therapeutics.

12. As a new product a-butoXy- -quinolinecarboxylic acid diethyl-amino-ethyleneamide of the formula CzHs C ONHCH2 CH2N/ crystallizing from petroleum ether in colorless crystals, melting at 6 0., soluble in organic solvents and forming neutral salts with acids, soluble in water which product is useful in therapeutics.

In witness whereof I have hereunto signed my name this 10th day of December 1927 V KARL MIESCHER. 

